Penile Cancer Mortality in Brazil: Are We Making Progress?

PURPOSE: This study aims to analyze the trends in mortality rates from penile cancer (PeC) and the treatment modalities adopted in Brazil over recent years. MATERIALS AND METHODS: Death records for PeC cases (International Classification of Diseases, version 10 C60) and treatment modalities were extracted from the DATASUS database. A joinpoint regression analysis was conducted to examine the data. RESULTS: A total of 7,848 deaths due to PeC were recorded in Brazil between 1996 and 2020. Increasing mortality trends were observed, with an average annual percentage change (AAPC) of 0.91 (0.6-1.2; P < .001). The North and Northeast regions had the highest age-standardized mortality rates (ASMRs) and AAPCs. From 2008 to 2020, the ASMR in the Northeast region remained stable, whereas the North region surpassed it. The Southeast region exhibited a significant downward trend, with an AAPC of -0.91 (-1.3 to -0.5; P < .001). Penile biopsies declined and were more frequent in the southeastern region. A total of 8,498 penile amputations were performed, with 39.4% and 29.1% conducted in the Southeast and Northeast regions, respectively. CONCLUSION: Brazil has experienced increasing mortality trends in PeC over the past 2 decades. Low schooling, married, and young men from the North or Northeast regions represent the majority of deaths. Urgent efforts are needed to enhance the diagnosis and treatment of PeC to prevent and reduce mortality rates in the country.

Case report of penile squamous cell carcinoma continuous treatment with BRCA2 mutation.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a highly aggressive malignancy with a poor prognosis. BRCA1/2 mutations are associated with impaired DNA double-strand break repair and are among the common mutations in penile cancer, potentially paving the way for poly ADP-ribose polymerase inhibitor therapy. CASE PRESENTATION: We report a 65-year-old male with PSCC who progressed to thigh metastasis at 10 months after partial penectomy. Next-generation sequencing showed that the penis primary lesion and metastatic thigh lesion harboured a BRCA2 mutation. Chemotherapy plus immunotherapy was used for treatment, and the thigh metastasis was found to involve no tumour. Progression-free survival (PFS) lasted for 8 months until the appearance of lung metastasis. Afterwards, the patient benefited from second-line therapy of olaparib with pembrolizumab and anlotinib, and his disease was stable for 9 months. The same BRCA2 was identified in the lung biopsy. Given the tumour mutation burden (TMB, 13.97 mutation/Mb), the patient received third-line therapy with nivolumab plus ipilimumab, but PFS only lasted for 3 months, with the appearance of right frontal brain metastasis. Then, the patient was treated with radiation sequential fluzoparib therapy as fourth-line treatment, and the treatment efficacy was evaluated as PR. Currently, this patient is still alive. CONCLUSIONS: This is the first report of penile cancer with BRCA2 mutation, receiving a combination treatment with olaparib and experiencing a benefit for 9 months. This case underscores the pivotal role of BRCA2 in influencing treatment response in PSCC, providing valuable insights into the application of targeted therapies in managing recurrent PSCC with BRCA2 alterations. This elucidation establishes a crucial foundation for further research and clinical considerations in similar cases.

Penile cancer care in the Netherlands: increased incidence, centralisation, and improved survival.

OBJECTIVE: To evaluate penile squamous cell carcinoma (PSCC) incidence and centralisation trends in the Netherlands over the past three decades, as well as the effect of centralisation of PSCC care on survival. PATIENTS AND METHODS: In the Netherlands PSCC care is largely centralised in one national centre of expertise (Netherlands Cancer Institute [NCI], Amsterdam). For this study, the Netherlands Cancer Registry, an independent nationwide cancer registry, provided per-patient data on age, clinical and pathological tumour staging, follow-up, and vital status. Patients with treatment at the NCI were identified and compared to patients who were treated at all other centres. The age-standardised incidence rate was calculated with the European Standard Population. The probability of death due to PSCC was estimated using the relative survival. Multivariable Cox regression analysis was performed to evaluate predictors of survival. RESULTS: A total of 3160 patients were diagnosed with PSCC between 1990 and 2020, showing a rising incidence (P < 0.001). Annual caseload increased at the NCI (1% in 1990, 65% in 2020) and decreased at other (regional) centres (99% to 35%). Despite a relatively high percentage of patients with T2-4 (64%) and N+ (33%) at the NCI, the 5-year relative survival was higher (86%, 95% confidence interval [CI] 82-91%) compared to regional centres (76%, 95% CI 73-80%, P < 0.001). Patients with a pathological T2 tumour were treated with glans-sparing treatment more often at the reference centre than at the regional centres (16% vs 5.0%, P < 0.001). After adjusting for age, histological grading, T-stage, presence of lymph node involvement and year of diagnosis, treatment at regional centres remained a predictor for worse survival (hazard ratio 1.22, 95% CI 1.05-1.39; P = 0.006). CONCLUSION: The incidence of PSCC in the Netherlands has been gradually increasing over the past three decades, with a noticeable trend towards centralisation of PSCC care and improved relative survival rate.

SPP1 is associated with adverse prognosis and predicts immunotherapy efficacy in penile cancer.

BACKGROUND: The effect of SPP1 in squamous cell carcinoma of the penis (PSCC) remained unknown. We attempted to clarify the function of the SPP1 gene in PSCC. METHOD: Eight paired penile cancer specimens (including penile cancer tissue, paracancerous tissue, and positive lymph node tissue) subjected to whole transcriptome sequencing were analysed to identify differentially expressed genes. We used immunohistochemistry to detect the expression of SPP1 protein and immune cell related proteins in penile cancer tissue. Then, we performed weighted gene coexpression network analysis (WGCNA) to identify the genes related to SPP1 in penile cancer tissue and positive lymph node tissue. Based on the GSE57955 dataset, the CIBERSORT and ssGSEA algorithms were carried out to investigate the immune environment of PSCC. GSVA analysis was conducted to identify the signaling pathways related to SPP1 subgroups. Enzyme-linked immunosorbent assay (ELISA) method was adopted to detect SPP1 level in the serum of 60 patients with penile cancer. RESULTS: Differential analysis indicated that SPP1 was the most differentially upregulated gene in both penile cancer tissues and positive lymph node tissues. Survival analysis suggested that the prognosis of the low-SPP1 group was significantly poorer than that of the high-SPP1 group. Subsequently, immune-related bioinformatics showed that SPP1 was significantly associated with B cells, CD8 + T cells, CD4 + T cells, macrophages, helper T cells, neutrophils and dendritic cells. The immunohistochemical results showed that the high-SPP1 group was characterized by relatively high expression of CD16 and relatively low expression of CD4. GSVA analysis indicated that high-SPP1 group was significantly associated with immune-related pathways such as PD-L1 expression and the PD-1 checkpoint pathway in cancer and the TNF signaling pathway. ELISA demonstrated that the serum level of SPP1 in patients with positive lymph node metastasis of penile cancer was significantly higher than that in patients with negative lymph node metastasis of penile cancer. CONCLUSION: Our study shows that the SPP1 gene might be an effective biomarker for predicting the prognosis and the efficacy of immunotherapy in PSCC patients.

Centralizing Penile Cancer Care in Germany and Austria: Just a Dream or a Fast-Approaching Reality? Results of a Survey Study among Urological Department Chairs and Modeling of Real Treatment Numbers of Penile Cancer Patients.

INTRODUCTION: In countries characterized by a centralization of therapy management, patients with penile cancer (PeCa) have shown improvements in guideline adherence and ultimately, improved carcinoma-specific survival. Germany and Austria (G + A) have no state-regulated centralization of PeCa management, and the perspectives of urological university department chairs (UUDCs) in these countries, who act as drivers of professional and political developments, on this topic are currently unknown. METHODS: Surveys containing 36 response options, including specific questions regarding perspectives on PeCa centralization, were sent to the 48 UUDC in G + A in January 2023. In addition to analyzing the responses, closely following the CROSS checklist, a modeling of the real healthcare situation of in-house PeCa patients in G + A was conducted. RESULTS: The response rate was 75% (36/48). 94% and 89% of the UUDCs considered PeCa centralization meaningful and feasible in the medium term, respectively. Among the UUDCs, 72% estimated centralization within university hospitals as appropriate, while 28% favored a geographically oriented approach. Additionally, 97% of the UUDCs emphasized the importance of bridging the gap until implementation of centralization by establishing PeCa second-opinion portals. No country-specific differences were observed. The median number of in-house PeCa cases at the university hospitals in G + A was 13 (interquartile range: 9-26). A significant positive correlation was observed between the annual number of in-house PeCa cases at a given university hospital and the perspective of the UUDCs that centralization as meaningful by its UUDC (0.024). Under assumptions permissible for modeling, the average number of in-house PeCa cases in academic hospitals in G + A was approximately 30 times higher than in nonacademic hospitals. CONCLUSION: This study provides the first data on the perspectives of UUDCs in G + A concerning centralization of PeCa therapy management. Even without state-regulated centralization in G + A, there is currently a clear focusing of PeCa treatments in university hospitals. Further necessary steps toward a structured PeCa centralization are discussed in this manuscript.

[Clinical characteristics and prognostic factors of distant metastatic penile cancer].

OBJECTIVE: To investigate the clinical features of distant metastatic penile cancer (DMPC) and the factors influencing its prognosis. METHODS: We searched the Surveillance, Epidemiology and End Results Database for cases of DMPC diagnosed between 2004 and 2019, analyzed their clinical characteristics and the cancer-specific survival (CSS) rates relating to different factors using the Kaplan-Meier method and the differences among the variables by log-rank test. We determined the variables independently associated with CSS by Cox regression analysis. RESULTS: According to the inclusion criteria, 108 cases of DMPC were identified. The patients were mainly married White people, with a median CSS of 9 months, and 1-, 2- and 3-year CSS rates of 36.4%, 17.8% and 13.5%, respectively. Pairwise comparison showed no statistically significant differences in the median overall CSS among the patients in the surgery, chemotherapy and surgery + chemotherapy groups (8 mo vs 9 mo vs 13 mo, P > 0.05). Race was an independent factor affecting the prognosis of CSS. CONCLUSION: Distant metastatic penile cancer is a rare malignancy with poor prognosis, for which there have been no existing ideal treatment options.

Regional differences in penile cancer patient characteristics and treatment rates across the United States.

INTRODUCTION: We tested for regional-specific differences in patient, tumor and treatment characteristics as well as cancer-specific mortality (CSM) of squamous cell carcinoma of the penis (SCCP) patients, across the Surveillance, Epidemiology, and End Results (SEER) registries. METHODS: The SEER database (2000-2018) was used to tabulate patient (age at diagnosis, race/ethnicity), tumor (stage, grade, N-stage) and treatment characteristics (proportions of primary tumor surgery, local lymph node surgery, systemic therapy), according to 12 SEER registries. Multinomial regression models, as well as multivariable Cox regression models tested for CSM differences, adjusting for patient, tumor and treatment characteristics. RESULTS: In 5395 SCCP patients, registry-specific patient counts ranged from 2060 (38 %) to 64 (1 %). Differences across registries existed for race/ethnicity, stage, grade and N-stage. Additionally, in stage I-II SCCP patients, proportions of local tumor destruction (LTD) ranged from 19 % to 39 % and from 33 % to 61 % for partial penectomy. In stage III-IV SCCP patients, proportions of partial penectomy ranged from 40 % to 59 % and from 17 % to 50 % for radical penectomy. Local lymph node surgery ranged from 8 % to 24 % and proportions of systemic therapy ranged from 3 % to 14 %. Significant inter-registry differences remained, after adjustment for treatment proportions. Unadjusted five-year CSM ranged from 19 % to 32 %. In multivariable analyses, one registry exhibited significantly higher CSM (SEER registry 10, Hazard Ratio [HR] 1.48), relative to the largest reference registry (SEER registry 1, n = 2060). CONCLUSION: Important regional differences including patient, tumor and treatment characteristics exist for SCCP patients across SEER registries. After multivariable adjustment, no differences in CSM were recorded, with the exception of one registry.

A Prospective Study of Chemoradiotherapy as Primary Treatment in Patients With Locoregionally Advanced Penile Carcinoma.

PURPOSE: Neoadjuvant chemotherapy followed by surgery for locoregionally advanced penile carcinoma (LAPSCC) is associated with severe toxicity and a 1-year survival probability of ∼50%. We aimed to evaluate the safety and efficacy of chemoradiotherapy (CRT) as the primary treatment for LAPSCC and the association of high-risk human papillomavirus (hrHPV) with the outcome. METHODS AND MATERIALS: This was a prospective, single-center, single-arm study of CRT in LAPSCC, defined as a large/inoperable primary tumor, large palpable nodes, suspicion of extranodal extension or pelvic nodal involvement, and no distant metastases. CRT consisted of 49.5 Gy (33 × 1.5 Gy) on affected inguinal and pelvic areas combined with intravenous mitomycin C on day 1 and capecitabine on radiation days. Primary tumors and positron emission tomography/computed tomography-positive deposits received a boost of 59.4 Gy (33 × 1.8 Gy). The response was evaluated by 18F-fluorodeoxyglucose positron emission tomography/computed tomography. If feasible, patients with residual/recurrent disease underwent salvage surgery. The primary endpoint was 1-year progression-free survival (PFS), reached when 1-year PFS was ≥50%. Other endpoints were 2-year PFS, overall survival, and toxicity rates. Kaplan-Meier survival curves were compared using the log-rank test. RESULTS: Thirty-three patients were included: 29 (88%) with stage IV disease (T4 any-N M0 and/or any-T N3 M0) and 8 (24%) with hrHPV-positive disease. Median follow-up was 41 months. Thirty-two completed CRT. Eleven (33%) experienced ≥1 grade 3 treatment-related adverse event. There were no grade 4 or 5 treatment-related events. Twenty-four patients (73%) responded, including 13 (39%) complete responses. Nine patients (27%) underwent salvage surgery, and an additional 8 patients underwent later surgery (together 52%). One- and 2-year PFS were 34% and 31%, respectively. One- and 2-year overall survival were 73% and 46%, respectively. No significant difference between patients with hrHPV-positive and -negative tumors was observed. CONCLUSIONS: CRT is a viable treatment option for LAPSCC with acceptable toxicity. CRT can result in an enduring response. If patients have residual tumor, salvage surgery is feasible. HrHPV status was not associated with outcomes.

Evaluation of Health-Related Quality of Life in Patients Receiving Treatment for Penile Cancer: A Single-Center Cross- Sectional Study.

INTRODUCTION: Penile cancer is one of the uncommon types of cancer in men. The treatment could significantly impact a patient's quality of life (QOL), leading to difficulties in fulfilling life functions. METHODS: This descriptive observational study aimed to describe a situation using a cross-sectional design objectively. The population of this study was all patients with a diagnosis of penile cancer who underwent therapy at the Haji Adam Malik Hospital from September 2020 to September 2021. Quality of life was assessed using EORTC QLQ-C30. RESULTS: The respondents' mean age and standard deviation were 54.44 and 8.647 years, respectively. The youngest was 38 years, while the oldest age was 64 years. Most respondents had no history of circumcision (55.6%). All respondents had a poor QOL based on the 28 components in the questionnaire. This study showed that erectile function, changes in sexual function, and overall sexual function were correlated with health-related quality of life (HRQoL) post-treatment. In general, lack of sexual activity is the primary factor responsible for decreasing HRQoL in penile cancer patients. It has been reported that 70% of patients experienced a negative impact on sexuality post-treatment. CONCLUSION: The quality of life in patients receiving treatment for penile cancer at RSUP H. Adam Malik, Medan, was poor. It is associated with a lack of sexual activity.

2022 European guideline for the management of balanoposthitis.

BACKGROUND: This guideline is an update to the 2014 edition of the European guideline for the management of balanoposthitis. Balanoposthitis describes inflammation of the glans penis and prepuce and is caused by a range of disparate conditions including infection, dermatoses and premalignancy. OBJECTIVE: The main objectives of this guideline are to aid recognition of the symptoms and signs and complications of penile skin conditions and to offer recommendations on the diagnostic tests and treatment for a selected group of these conditions. METHODS: The previous guideline was updated following a literature review and priority was given to randomized controlled trial and systematic review evidence. RESULTS: The updated guideline includes amended management for infective balanitis to provide clear guidance for Group A streptococcal infections, management of on going Lichen sclerosus (to include circumcision and supportive management to reduce the recurrence of genital herpes and warts), additional regimens for Zoonoid change, use of calcineurin inhibitors in management and risk of premalignancy and change of nomenclaturefrom Premalignant conditions to Penile Intraepithelial neoplasia (PeIN). CONCLUSION: Balanoposthitis has a widerange of causes high quality evidence specific to the management of penile disease is not available for all the conditions described.

European Association of Urology-American Society of Clinical Oncology Collaborative Guideline on Penile Cancer: 2023 Update.

CONTEXT: Penile cancer is a rare disease but has a significant impact on quality of life. Its incidence is increasing, so it is important to include new and relevant evidence in clinical practice guidelines. OBJECTIVE: To provide a collaborative guideline that offers worldwide physician and patient guidance for the management of penile cancer. EVIDENCE ACQUISITION: Comprehensive literature searches were performed for each section topic. In addition, three systematic reviews were conducted. Levels of evidence were assessed, and a strength rating for each recommendation was assigned according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology. EVIDENCE SYNTHESIS: Penile cancer is a rare disease but its global incidence is increasing. Human papillomavirus (HPV) is the main risk factor for penile cancer and pathology should include an assessment of HPV status. The main aim of primary tumour treatment is complete tumour eradication, which has to be balanced against optimal organ preservation without compromising oncological control. Early detection and treatment of lymph node (LN) metastasis is the main determinant of survival. Surgical LN staging with sentinel node biopsy is recommended for patients with a high-risk (≥pT1b) tumour with cN0 status. While (inguinal) LN dissection remains the standard for node-positive disease, multimodal treatment is needed in patients with advanced disease. Owing to a lack of controlled trials and large series, the levels of evidence and grades of recommendation are low in comparison to those for more common diseases. CONCLUSIONS: This collaborative penile cancer guideline provides updated information on the diagnosis and treatment of penile cancer for use in clinical practice. Organ-preserving surgery should be offered for treatment of the primary tumour when feasible. Adequate and timely LN management remains a challenge, especially in advanced disease stages. Referral to centres of expertise is recommended. PATIENT SUMMARY: Penile cancer is a rare disease that significantly impacts quality of life. While the disease can be cured in most cases without lymph node involvement, management of advanced disease remains challenging. Many unmet needs and unanswered questions remain, underlining the importance of research collaborations and centralisation of penile cancer services.

Melanoma of glans penis and urethra: A case report and systematic review of the literature of a rare and complex neoplasm.

OBJECTIVE: To evaluate the features and prognosis of melanoma of glans penis and urethra, with the presentation of a significant case report. MATERIALS AND METHODS: A systematic literature review was performed using the MEDLINE (PubMed) and Cochrane Libraries databases to identify all cases of male mucosal melanoma reported. RESULTS: Two hundred fifty-two patients with male mucosal primary melanoma were found. Glans penis and fossa navicularis as primary site includes the 81.6% of all lesions considered. Median Breslow's depth is 2.1 mm, whereas nine in situ melanomas have been reported. At the diagnosis, the disease was at a non-localized stage in 21.4% for glans penis melanomas and 11.7% urethral lesions, respectively. The 2 and 5-year survival for glans melanoma is 62.5% and 38.4%; higher rates were observed in the 2012-2020 period (76% and 58.8%, respectively). Two-year survival for urethral melanomas is 66.7%, while 5-year survival is 12.5%. 22 patients survived over 5 years with a Breslow's depth reported always < 3.3 mm. CONCLUSION: Melanoma of the glans penis and urethra is a rare neoplasm associated with a poor prognosis, however recent reports show higher survival rates. Surgery remains the mainstay for a localized disease. Taking into account the small number of cases reported, topical imiquimod seems to be a valid non-surgical alterative for melanoma in situ. The use of immunotherapy and targeted therapy should be considered only in an adjuvant setting according to the recommendations of cutaneous melanoma; however, additional clinical data on male mucosal melanoma are needed to draw definitive conclusions.

Molecular Pathogenesis of Penile Squamous Cell Carcinoma: Current Understanding and Potential Treatment Implications.

CONTEXT.­: Penile squamous cell carcinomas (PSCCs) are divided into tumors that are human papillomavirus (HPV) associated and those that are non-HPV associated. HPV and non-HPV PSCCs each display unique pathogenic mechanisms, histologic subtypes, and clinical behaviors. Treatment of localized PSCC tumors is linked to significant physical and psychological morbidity, and management of advanced disease is often treatment refractory. The identification of novel actionable mutations is of critical importance so that translational scientists and clinicians alike can pursue additional therapeutic options. OBJECTIVE.­: To provide an update on the molecular pathogenesis associated with PSCC. A special emphasis is placed on next-generation sequencing data and its role in identifying potential therapeutic targets. DATA SOURCES.­: A literature review using the PubMed search engine to access peer-reviewed literature published on PSCC. CONCLUSIONS.­: Our understanding of the genetic and molecular mechanisms that underlie PSCC pathogenesis continues to evolve. PSCC tumorigenesis is mediated by multiple pathways, and mutations of oncogenic significance have been identified that may represent targets for personalized therapy. Preliminary results of treatment with immune checkpoint inhibition and tyrosine kinase inhibitors have produced variable clinical results. Further insight into the pathogenesis of PSCC will help guide clinical trials and develop additional precision medicine approaches.

Immune landscape and immunotherapy for penile cancer.

Penile cancer is a rare malignancy and usually refers to penile squamous cell carcinoma (PSCC), which accounts for more than 95% of all penile malignancies. Although organ-sparing surgery is an effective treatment for early-stage PSCC, surgical intervention alone is often not curative for advanced PSCC with metastases to the inguinal and/or pelvic lymph nodes; thus, systemic therapy is required (usually platinum-based chemotherapy and surgery combined). However, chemotherapy for PSCC has proven to be of limited efficacy and is often accompanied by high toxicity, and patients with advanced PSCC usually have poor prognosis. The limited treatment options and poor prognosis indicate the unmet need for advanced PSCC. Immune-based therapies have been approved for a variety of genitourinary and squamous cell carcinomas but are rarely reported in PSCC. To date, several studies have reported high expression of PDL1 in PSCC, supporting the potential application of immune checkpoint inhibitors in PSCC. In addition, human papillomavirus (HPV) infection is highly prevalent in PSCC and plays a key role in the carcinogenesis of HPV-positive PSCC, suggesting that therapeutic HPV vaccine may also be a potential treatment modality. Moreover, adoptive T cell therapy (ATC) has also shown efficacy in treating advanced penile cancer in some early clinical trials. The development of new therapeutics relies on understanding the underlying biological mechanisms and processes of tumor initiation, progression and metastasis. Therefore, based on the interest, we reviewed the tumor immune microenvironment and the emerging immunotherapy for penile cancer.

French AFU Cancer Committee Guidelines - Update 2022-2024: penile cancer.

OBJECTIVE: To update French oncology guidelines concerning penile cancer. METHODS: Comprehensive Medline search between 2020 and 2022 upon diagnosis, treatment and follow-up of testicular germ cell cancer to update previous guidelines. Level of evidence was evaluated according to AGREE-II. RESULTS: Epidermoid carcinoma is the most common penile cancer histology. Physical examination is mandatory to define local and inguinal nodal cancer stage. MRI with artificial erection can help to assess deep infiltration in cases of organsparing intention. Node negative patients (defined by palpation and imaging) will present micro nodal metastases in up to 25% of cases. Invasive lymph node assessment is thus advocated except for low risk patients. Sentinel node dynamic biopsy is the first line technique. Modified bilateral inguinal lymphadenectomy is an option with higher morbidity. 18-FDG-PET is recommended in patients with palpable nodes. Chest, abdominal and pelvis computerized tomography is an option. Fine needle aspiration (when positive) is an easy way to assess inguinal palpable node pathological involvement. Its results determine the type of lymphadenectomy to be performed (for diagnostic or curative purposes). Treatment is mostly surgical. Free margins status is essential, but it also has to be organ-sparing when possible. Brachytherapy and topic agents can cure in selected cases. Lymph node assessment should be synchronous to the removal of the tumour when possible. Limited inguinal lymph node involvement (pN1 stage) can be cured with the only lymphadenectomy. In case of larger lymph node stage, one should consider multidisciplinary treatment including chemotherapy and inclusion in a trial. CONCLUSIONS: Penile cancer needs demanding surgery to be cured, surrounded by chemotherapy in node positive patients. Lymph nodes involvement is a major prognostic factor. Thus, inguinal node assessment cannot be neglected.

Immune-based therapies in penile cancer.

Penile cancer is a rare genitourinary malignancy that is associated with poor outcomes and severely limited therapeutic options that are generally non-curative when used to treat localized disease with high-risk features or advanced disease. To address the unmet need for treatment modalities with increased effectiveness, immune-based therapies such as immune-checkpoint blockade, human papilloma virus (HPV)-directed vaccines and adoptive T cell therapies have emerged as potential treatment options for advanced penile cancer. A diverse array of immune cells such as cytotoxic T lymphocytes (CTLs), tumour-associated macrophages and myeloid-derived suppressor cells have been shown to infiltrate penile cancer tumours, with distinct immune landscapes being demonstrated in HPV-positive compared with HPV-negative tumours. Study results have also demonstrated the prognostic value of immune cells such as tumour-associated macrophages, immune markers such as programmed death ligand-1, and HPV-status in penile cancer. Taken together, these findings underscore the clinical relevance of the tumour immune microenvironment as a source of both prognostic indicators and potential therapeutic targets for immune-based therapies. Current evidence regarding the safety and efficacy of immune-based therapies is limited in penile cancer, but a number of clinical and preclinical studies are ongoing to evaluate these therapies in this disease based on promising results from studies in other malignancies, including other squamous cell carcinomas. In addition, an opportunity exists to combine immune-based therapies with existing lines of systemic therapy to offer the most benefit to patients with advanced penile cancer. Future work should focus on expansion of preclinical models for immune-based drug discovery.